FIGURE 16-5 Model of Ski-mediated down-regulation of Smad transcription-activating function. Ski represses Smad function by binding directly to Smad4. Since the Ski-binding domain on Smad4 significantly overlaps with the Smad4 MH2 domain required for binding the phosphorylated tail of Smad3, binding of Ski disrupts the normal interactions between Smad3 and Smad4 necessary for transcriptional activation. In addition, Ski recruits the protein N-CoR, which binds directly to mSin3A; in turn, mSin3A interacts with histone deacetylase (HDAC), an enzyme that promotes histone deacetylation on nearby promoters, repressing gene expression (see Chapter 9). As a result of both processes, transcription activation induced by TGF-β and mediated by Smad complexes is shut down. The related protein SnoN functions similarly to Ski in repressing TGF-β signaling. See J. Deheuninck and K. Luo, 2009, Cell Res. 19:47.